AGFG1 通过破坏细胞内胆固醇稳态来促进 PDAC 进展，从而增加胆固醇生物合成。
AGFG1 increases cholesterol biosynthesis by disrupting intracellular cholesterol homeostasis to promote PDAC progression.
发表日期：2024 Jul 30
作者：
Zonghao Duan, Minwei Yang, Jian Yang, Zheng Wu, Yuheng Zhu, Qinyuan Jia, Xueshiyu Ma, Yifan Yin, Jiahao Zheng, Jianyu Yang, Shuheng Jiang, Lipeng Hu, Junfeng Zhang, Dejun Liu, Yanmiao Huo, Linli Yao, Yongwei Sun
来源：
CANCER LETTERS
摘要：
胆固醇代谢重编程已被公认为癌症的一个新特征。胰腺导管腺癌（PDAC）是一种需要大量胆固醇才能快速生长的癌症。探讨PDAC中胆固醇代谢稳态受到干扰的潜在机制。TCGA数据库证实了PDAC与胆固醇之间的相关性。在 TCGA 和 GEO 数据集中发现了表达和临床关联。采用AGFG1的敲低和过表达来进行功能研究。 RNA测序、胆固醇检测、透射电镜、免疫共沉淀、免疫荧光等。生物信息学分析表明，AGFG1是PDAC中与胆固醇代谢呈正相关的一个基因。随后发现 AGFG1 表达与 PDAC 预后不良相关。 AGFG1 敲低导致体外和体内肿瘤细胞增殖减少。通过RNA测序，我们发现AGFG1表达上调导致细胞内胆固醇生物合成增强。 AGFG1 敲低抑制了胆固醇生物合成和内质网中胆固醇的积累。从机制上讲，我们证实AGFG1与CAV1相互作用，重新定位胆固醇以进行胆固醇生物合成，从而导致细胞内胆固醇代谢紊乱。我们的研究证明了AGFG1通过扰乱PDAC中胆固醇代谢稳态而发挥促肿瘤作用。我们的研究提出了基于 PDAC 中胆固醇代谢的癌症治疗方法的新视角。版权所有 © 2024。由 Elsevier B.V. 出版。
Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored.The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism.AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism.Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.Copyright © 2024. Published by Elsevier B.V.